CFTR variants linked to a second type of Cystic Fibrosis that does not affect the lungs.

A paper published in PLoS Genetics by LaRusch and colleagues from the North American Pancreatitis Study II (NAPS2) provides compelling evidence of a group of pathogenic mutations in the CFTR gene that increase the risk for chronic pancreatitis, but not lung disease. CFTR is a molecule that is expressed on epithelial cells that separate the fluids of the body from the outside world. CFTR is a channel that allows negatively charged ions (i.e. anions such as chloride [Cl-] and bicarbonate [HCO3-]) to be pushed from the endothelial cells interior out of the body by a strong electrical charge (the inside of the cell has a negative charge and like charges repulse). The build up of ions outside of the cells cause an increase in osmotic pressure, pulling water and sodium out of the body as well – resulting in fluid secretion. The recent discovery demonstrated that when a molecule inside the epithelial cells called WNK1 is activated, it causes the CFTR molecule to change from the normal chloride channel, to a bicarbonate channel. The new discovery is that 9 mutations were discovered that prevent WNK1 from making the switch, so cells that use CFTR for bicarbonate secretion, including the pancreas, sinuses and male reproductive organs, do not work properly. The pancreas may develop cysts and fibrosis – just like in severe mutations that totally destroy CFTR function and cause classic cystic fibrosis. Download the full paper at PLoS Genetics, or read a more detailed newspaper article from the Pittsburgh Post-Gazette.

Secretin released for clinical use:

May 14, 2014. The FDA notified ChiRhoClin officials today in writing that they are permitting regulatory discretion to release secretin to the medical community, in order to alleviate the current critical shortage of ChiRhoStim (human secretin for injection) while the manufacturing facility continues to wait for FDA approval. All test results and media fills show no contamination at the manufacturing facility. The FDA instructed ChiRhoClin to supply a microbial filter with each vial ordered to provide an additional level of assurance to protect against any theoretical possibility of microbiological contamination. It is expected that secretin shipments will be shipped by the end of May.

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July 23 (PM) to July 25, 2014. The focus is on complications of chronic pancreatitis – pancreatogenic diabetes (T3cDM) – pancreatic cancer development and detection. Annual meeting of CAPER and INSPPIRE. Brufsky Award and lecture for clinical excellence in pancreatic cancer research. Workshops and working group meetings for INSPPIRE, North American Pancreatic Study Group (NAPS2-AA, NAPS3), Acute Pancreatitis Working Group, and more…! “In addition to a fantastic program, the cost of having PancreasFest in Pittsburgh is low enough that I can afford to bring my students and post-docs to learn, present their work and meet the leaders in the field” – Miklos Sahin-Toth MD PhD.

Recommendations from PancreasFest:

The Guidance statements from are now published in Pancreatology

“Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: Recommendations from PancreasFest 2012“. These specifically address issues surrounding when and how to screen for diabetes, including Type 3c (pancreatogenic diabetes).(Click here for Abstract).

“Total pancreatectomy and islet autotransplantation in chronic pancreatitis: Recommendations from PancreasFest” These recommendations guid physicians in the evaluation and management of patients before, and after TPIAT. Click here for Abstract”

The Carboxypeptidase A1 (CPA1) gene is a chronic pancreatitis susceptibility gene with a novel mechanism of disease.

Mutations in CPA1 are linked to patients with nonalcoholic chronic pancreatitis, especially with early age of onset (see Witt et al, Nature Genetics, PMID 23955596). Carboxypeptidase A1 is pancreatic digestive enzyme that hydrolyzes C-terminal peptide bonds in dietary polypeptides that are exposed by chymotrypsins and elastases. It is the most abundant digestive enzyme after trypsin, and contributes up to 10% of the total protein. Risk of chronic pancreatitis is unrelated to trypsin. DNA sequencing of all ten CPA1 exons in 944 German cases and 3,938 control reveled 35 different mutations. Functional studies in the laboratory of Miklós Sahin-Tóth MD PhD (Boston Univ.) showed that many of the variants had less than 20% of expected activity and were not secreted from experimental cells. This suggests that the mutated peptides were miss-folding, causing stress inside of the endoplasmic reticulum. The low activity mutants were found in 3.1% of cases compared to 0.1% of controls (OR = 25). The finding was replicated in 3 other groups, and found to be especially prevalent in children.

NIDDK-NCI Workshop on Pancreatitis-Diabetes-Pancreatic Cancer: REPORT

June 12-13, 2013. Bethesda MD. By all accounts, the PDPC conference was an overwhelming success. A full report will be published in the November issue of Pancreas. The most important take-away points are that relationship between pancreatitis, diabetes and pancreatic cancer are complex, and that evaluation of human data to assess possible connections requires the proper control population. The problem is further complicated by “reverse causality”; pancreatitis is a risk for pancreatic cancer and pancreatic cancer can cause acute and chronic pancreatitis: diabetes mellitus is a risk for pancreatic cancer, but pancreatic cancer can also cause diabetes – up to two years before it can be seen on CT scan. The combination of pancreatitis and diabetes results in higher risk of pancreatic cancer than either disease alone. Also, it was clear that assessing the effects of diabetes treatment on pancreatic cancer risk was critically dependent on the control population, since the risk of patients with diabetes is independently increase already. The risk may be especially high in patients with pancreatogenic (Type 3c) diabetes, but this type of diabetes has not been tested for in big epidemiology studies.

Data presented from randomized controlled trials of GLP-1 and DPP-4 anti-diabetes agents did not appear to indicate any risk for pancreatic cancer above matched control populations with the same diseases. The FDA also presented their methods of assessing risk in human studies and by assessing and replicating animal studies, and they did not report an increased cancer risk with use of either GLP-1 agonists or DPP-4 antagonists. See Program Link.

Breakthrough: Alcohol, CLDN2 & Chronic Pancreatitis in men:

A genetic link between alcohol drinking and chronic pancreatitis in men has been discovered. An advanced online report has was published (see PMID: 23143602 ) that largely explains why men have chronic alcoholic pancreatitis more often then women. A region on Chromosome X called the “CLDN2 locus” seems to cause a rapid progression from acute pancreatitis to chronic pancreatitis, rather than recovery, in persons who continue to drink alcohol after acute pancreatitis. About 4% of men in the United states are at risk because they have BOTH the X-factor and are drinking alcohol (>4 drinks per day). Men have the XY chromosome pair, while women have XX. Having two X chromosomes, with at least one being normal protects women – only 0.6% of women in the United States are at risk. The study also showed that a genetic factor on chromosome 7 that decreases expression of trypsin reduces the risk of recurrent acute and chronic pancreatitis. (for more information see UPMC Press Release)

PRSS1 – Website.

A new web site has been launched to provide information on the functional consequence of various cationic trypsinogen (PRSS1) mutations. The site is maintained by Dr. Miklos Sahin-Toth and Dr. Balazs Nemeth. Click hereto visit.

2014 Pancreas Meeting Calendar.

This information is designed as a tool for background for pancreatic disorders and is not designed to serve as sole medical advice or meant to replace a full medical evaluation. Please consult your personal physician for additional information before making any changes to your diet, lifestyle, or medical treatment.